Postoperative delirium, an acute confusional state caused by an underlying physiological disturbance following surgery and characterized by sleep/wake cycle disturbances, is a serious public health problem that disproportionately affects older people, particularly those with underlying cognitive impairment. Delirium is associated with many negative outcomes including: increased mortality, longer hospital stays, increased institutionalization after acute care hospitalization, worse cognitive and physical outcomes (both short- and long-term), and significant distress for patients and their families. Estimates of healthcare costs due to all episodes of delirium among the elderly range from $38 to $152 billion/year. Aging of the population means increasing numbers of older adults are undergoing surgery ? making postoperative delirium prevention an urgent priority. This proposal provides innovation by examining the delirium preventive effects of the melatonin agonist, ramelteon, by conducting a randomized, double blind controlled clinical trial in 80 adults, >65 years, undergoing planned orthopaedic reconstructive surgery of non-infected knee or hip joint under general anesthesia. Ramelteon/placebo will be administered orally the evening before surgery and at bedtimes on the day of surgery and postoperative day (POD) 1. The specific aims of this exploratory phase II trial include the comparison of 1) postoperative delirium incidence, and 2) adverse events in active treatment and placebo. Delirium prevention may occur through multiple mechanisms including maintenance of sleep and diurnal rhythms, anti-inflammatory effects, and/or dopamine blockade. In addition, the proposal examines both early (PACU) and late (POD 1 and 2) effects of ramelteon on postoperative delirium prevention. A positive trial will have substantial clinical and public health impact by offering an easy-to-use and safe perioperative intervention to prevent postoperative delirium in older surgical patients and guiding translational work to explore new mechanisms in the understanding the causes of postoperative delirium.